Is COL2A1 p.Glu142Asp (c.426A>T) pathogenic?

COL2A1 p.Glu142Asp (c.426A>T) is classified Benign/Likely benign in COL2A1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-05-09). AlphaMissense: likely benign (0.0769); Common (popmax 5.51%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with connective tissue disorder.

What condition is associated with COL2A1 p.Glu142Asp (c.426A>T)?

COL2A1 p.Glu142Asp (c.426A>T) is associated with connective tissue disorder, Stickler syndrome type 1, type 2 collagenopathy (ClinVar).

What do computational predictors say about COL2A1 p.Glu142Asp (c.426A>T)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

COL2A1 p.Glu142Asp

Q: How common is COL2A1 p.Glu142Asp (c.426A>T) in the general population?

COL2A1 p.Glu142Asp (c.426A>T) is common (popmax 5.51%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.426A>T · rs34392760 · VCV258239

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.51%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.81 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.51% European (non-Finnish) · 65,068/1,179,992 alleles

Filtering AF 5.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.46%

Overall 4.7% 75,881/1,614,054 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	7.16%	14
European (non-Finnish)grpmax	5.51%	18
Middle Eastern	5.49%	18
Remaining individualsnot grpmax-eligible	4.5%	22
Admixed American	3.13%	32
Amishnot grpmax-eligible	2.96%	34
Finnishnot grpmax-eligible	2.8%	36
South Asian	1.31%	76
African / African-American	0.874%	114
East Asian	0.0111%	8,978

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COL2A1
Protein: p.Glu142Asp
Coding: c.426A>T
MANE Select: NM_001844
dbSNP: rs34392760
Type: single nucleotide variant
Location: chr12:47997874 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 142: the 'disordered' region; a UniProt-annotated variant site (in)

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1 type 2 collagenopathy

Similar variants

COL2A1 c.1222-2A>G Pathogenic ★★ same condition
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1581+1G>A Likely pathogenic ★★ same condition
COL2A1 c.1833+1G>A Pathogenic ★★ same condition
COL2A1 c.1887+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1888-2A>C Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/col2a1-p-glu142asp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown